ABSTRACT The human pathogen Streptococcus mutans is a major etiological agent associated in dental caries and a common causative agent of infective endocarditis (IE). Evidence has recently emerged that strains of S. mutans producing the collagen binding protein Cnm may be associated with more severe cases of IE and with the development of other extra-oral pathologies including hemorrhagic stroke and IgA nephropathy. While Cnm-producing strains are not prevalent in the oral cavity, crosss-sectional clinical studies have linked infection with cnm+ S. mutans with increased caries incidence and severity. Moreover, studies conducted in our laboratory have showed that S. mutans strains producing Cnm can more efficiently adhere to collagen-rich tissues present in heart valves and in teeth (i.e. dentin) ex vivo, and are able to invade oral epithelial and heart endothelial cells in vitro. Using the rabbit IE and rat caries models, we confirmed that Cnm is an important virulence factor indicating that S. mutans strains that produce Cnm can be hypervirulent. The data obtained thus far indicate that the properties conferred by Cnm enables S. mutans persistence and virulence in the oral cavity that could also facilitate systemic dissemination and infection. Using molecular and biochemical approaches, we found that Cnm is posttranslationally modified by a newly identified glycosylation complex that was named Pgf. Loss of the Pgf system impaired Cnm function by affecting its stability. We also found that Cnm has amylodoigenic properties albeit the impact of amyloid formation by Cnm on collagen-binding and related functions is presently unknown. We propose that the glycosylation state and amyloidogenic form of Cnm may contribute to its function by promoting protein stability (glycosylation) or by conferring novel properties (amyloid formation) to Cnm. The overarching hypothesis of this application is that cnm+ S. mutans strains are better equipped to colonize human tissues, including oral soft tissues and exposed dentin and teeth roots, and, therefore may be associated with more aggressive and reincident cases of caries, such as those found in early childhood caries. We postulate that oral infection by cnm+ S. mutans are linked to the most aggressive cases of caries, as well as to caries recurrence that cannot be explained by conventional risk factors such as high intake of sucrose-containing foodstuffs and poor oral hygiene. In this application, we will use biochemical, molecular, glycoproteomic and structural approaches to characterize Cnm as both a glycoprotein and an amyloidogenic protein, and the rat caries model to uncover the significance of Cnm in oral colonization, persistence and cariogenicity. The findings of this study will reveal additional facets associated with infection by different strains of S. mutans, which could lead to changes in current paradigms for assessing caries risk and ultimately help devise novel antimicrobial therapies.